The overall long term objective of this proposal is to determine whether individual nonpsychoactive constituents of Cannabis sativa (marijuana), alone or in combination, will provide safe, effective treatment for diseases characterized by acute and/or chronic inflammation. The medicinal use of marijuana has been limited by its psychoactivity and by induction of tolerance. Existence of nonpsychoactive marijuana constituents and development of synthetic cannabinoids encourage further research to identify nonpsychoactive plant components with antiinflammatory properties. A complete marijuana extract (CME) and pure nonpsychoactive cannabinoid and noncannabinoid Cannabis constituents will be tested in human whole blood models for their ability to influence production in vitro of inflammatory eicosanoids and cytokines. The antiinflammatory effects of oral administration of the CME and the pure nonpsychoactive Cannabis constituents will also be tested in a model of acute inflammation (induced by IL-1Beta and TNFalpha in a subcutaneous air pouch in rats), and a model of chronic inflammation (adjuvant induced polyarthritis in rats). Controls for experiments in vitro and studies in animals will include vehicle, dexamethasone, indomethacin, and a selective inhibitor of cyclooxygenase 2. A noncannabinoid, nonpsychoactive marijuana constituent termed cannflavin will be isolated using high-pressure liquid chromatography and tested in the in vivo models and in vitro systems. Successful completion of the proposed experiments should identify ways of harnessing important antiinflammatory properties of marijuana without the limiting adverse effects.